The reversible acetylation of the ε-amino groups of several lysine residues in the N-terminal histone tails mediates important conformational modifications in nucleosomes. These modifications influence the access of transcription factors to DNA and regulate gene expression (Davie, J. R. Curr Opin Genet Dev 1998, 8, 173-178; Ellis, L. et al. Mol Cancer Ther 2009, 8, 1409-1420). Two enzyme classes are involved in the process of acetylation and deacetylation of histones: histone acetyltransferases (HAT), which catalyse histone acetylation by acting as transcriptional co-activators, and histone deacetylases (HDAC).
After their recruitment to the promoter regions induced by transcription repressors and co-repressors such as Sin3, SMRT and N—CoR, histone deacetylases induce the formation of hypoacetylated histones and ultimately lead to transcriptional silencing (Wu, J. et al. Trends Biochem. Sci. 2000, 25, 619-623). The aberrant recruitment of histone deacetylases by oncogene proteins, or the disruption of the equilibrium between the activities of histone acetyltransferases and histone deacetylases are implicated in a series of pathologies, such as cancer, diseases of the central and peripheral nervous system, inflammatory diseases, infections, respiratory diseases, immune diseases, cardiovascular diseases, muscular disorders, fibrosis or psoriasis. The following (non exhaustive) selection of references demonstrate the involvement of HDACs in different diseases and the potential therapeutic benefit, which can be achieved by inhibiting them: Timmermann S. et al. Cell Mol Life Sci. 2001 58, 728-736; Huang, L. J. Cell. Physiol. 2006, 209, 611-616; Minucci, S. et al. Nature Reviews Cancer, 2006, 6, 38-51; Ouaissi, M. et al. J Biomed Biotechnol. 2006, 1-10; Sharma, P. et al. Schizophr. Res. 2006, 88, 227-231; Glozak M. A. et al. Oncogene. 2007, 26, 5420-5432; Elaut G. et al. Curr Pharm Des. 2007, 13, 2584-2620; Balakin K. V. et al. Anticancer Agents Med. Chem. 2007 7, 576-92; Lee H. B. et al. Kidney Int. Suppl. 2007, 106, S61-66; Morrison B. E. et al. Cell Mol Life Sci. 2007, 64, 2258-2269; Rasheed W. et al. Expert Rev Anticancer Ther. 2008, 8, 413-432; Kazantsev A. G. et al. Nat Rev Drug Discov. 2008, 7, 854-868; Haberland M. et al. Nat Rev Genet. 2009, 10, 32-42; Wiech N. E. et al. Curr Top Med. Chem. 2009, 9, 252-271; Rotili D. et al. Curr Top Med. Chem. 2009, 9, 272-291; Halili M. A. et al. Curr Top Med. Chem. 2009, 9, 309-319.
There has been a considerable effort to develop inhibitors of histone deacetylases in recent years and several classes of compounds have been found to have potent and specific activities in preclinical studies. Their clinical benefits, however, are limited by toxicity problems, poor pharmacokinetic properties, poor potency and lack of selectivity (Elaut G. et al. Curr Pharm Des. 2007, 13, 2584-2620; Vigushin, D. et al. Anti-Cancer Drugs 2002, 13, 1-13).
PCT applications WO 2007/061880, WO 2007/061978 and WO 2007/136605 (Merck) disclose spirocyclic compounds as HDAC inhibitors. Compounds disclosed in these patents and their biological activities were further described in Biorg Med Chem Lett 2008, 18, 6104-6109 and in Biorg Med Chem Lett 2009, 19, 1168-1172. Further spirocyclic HDAC inhibitors are disclosed in WO2009/127609.
The inventors have found now that certain substituted spirocyclic derivatives are highly potent inhibitors of the HDAC enzymes.